![PROMID: PFS
Treatment Naïve Midgut NETs
0"
0.25"
0.5"
0.75"
1"
0" 6" 12" 18" 24" 30" 36" 42" 48" 54" 60" 66" 72" 78" 84" 90"
HR="0.33"[95%"CI:"0.19–0.55]"
P=0.000017"
Propor;on"without"progression"
Time"(months)"
Octreo;de"LAR:"42"pa;ents"/"27"events"
"Median"15.6"months"[95%"CI:"11.0–29.4]"
"
"Placebo:"43""pa;ents"/"41"events"
"Median"5.9"months"[95%"CI:"5.5–9.1]"
Rinke et al, JCO 2009](https://image.slidesharecdn.com/july162016washingtondcsupportgroupfinal-drwolin-161025041301/85/Dr-Ed-Wolin-July-16-2016-DC-Neuroendocrine-Tumor-Support-Group-Presentation-18-320.jpg)
![CLARINET: Primary Efficacy Endpoint (PFS)
Data are from the ITT populaUon. P-value derived from straUfied log-rank test; HR derived from Cox proporUonal
hazards model.
HR, hazard raUo; ITT, intenUon to treat; PBO, placebo; PD, progressive disease; PFS, progression-free survival.
Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.
LanreoDde
32 events, 101 paDents
Median PFS not reached
Placebo
60 events,103 paDents
Median PFS= 18.0 months [95% CI: 12.1, 24.0]
0 3 6 9 12 18 24 27
0
10
20
30
40
50
60
70
80
90
100 PaDents alive and with no progression (%)
Time (months)
62%
22%
LanreoDde 120 mg vs. PBO
P <0.001 HR=0.47
[95% CI: 0.30, 0.73]
Progression-free survival (ITT populaDon*)
101 94 84 78 71 61
103 101 87 76 59 43
40
Numbers of paDents at risk of death or PD
26 0
0](https://image.slidesharecdn.com/july162016washingtondcsupportgroupfinal-drwolin-161025041301/85/Dr-Ed-Wolin-July-16-2016-DC-Neuroendocrine-Tumor-Support-Group-Presentation-20-320.jpg)
![SOM230–C2303
Pasireotide vs. Octreotide
0 3 6 9 12
Time, months
15 21 27
SurvivalProbability
0.0
0.2
0.4
0.6
0.8
1.0
Octreotide n/N = 20/56
Pasireotide n/N = 18/52
Censored
Kaplan-Meier median PFS
Pasireotide: 11.8 months, 95% CI [11.0–not reached]
Octreotide: 6.8 months, 95% CI [5.6–not reached]
Hazard ratio = 0.46, 95% CI [0.20–0.98]
Total events = 38
2
P = 0.045 (log-rank test)
Wolin et. al., A multicenter, randomized, blinded, phase III study of pasireotide LAR
versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with
disease-relatedsymptoms inadequately controlled by somatostatin analogs.
J Clin Oncol 31, 2013 (suppl; abstr 4031)](https://image.slidesharecdn.com/july162016washingtondcsupportgroupfinal-drwolin-161025041301/85/Dr-Ed-Wolin-July-16-2016-DC-Neuroendocrine-Tumor-Support-Group-Presentation-26-320.jpg)
![Progression-Free Survival
32Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
Hazard Ratio [95% CI]
0.209 [0.129 – 0.338]
p < 0.0001
N = 229 (ITT)
Number of events:
90
• 177Lu-Dotatate: 23
• Oct 60 mg LAR:
67
All progressions centrally confirmed and independently reviewed for eligibility
(SAP)
Octreotide LAR 60 mg
Median PFS: 8.4 months
177Lu-Dotatate
Median PFS: Not reached](https://image.slidesharecdn.com/july162016washingtondcsupportgroupfinal-drwolin-161025041301/85/Dr-Ed-Wolin-July-16-2016-DC-Neuroendocrine-Tumor-Support-Group-Presentation-32-320.jpg)
![RADIANT-3 PFS by Central Review*
* Independent adjudicated central review committee
• P-value obtained from stratified one-sided log rank test
• Hazard ratio is obtained from stratified unadjusted Cox model
Kaplan-Meier medians PFS
Everolimus: 11.4 months
Placebo: 5.4 months
Hazard ratio = 0.34; 95% CI [0.26-0.44]
P-value: <0.0001
No. of patients still at risk
Everolimus
Placebo
207
203
187
180
152
99
126
60
117
52
81
22
49
12
36
5
27
3
22
1
10
1
6
1
2
0
0
0
Time (months)
100
80
Percentageevent-free
Censoring Times
Everolimus (n/N = 95/207)
Placebo (n/N = 142/203)
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26](https://image.slidesharecdn.com/july162016washingtondcsupportgroupfinal-drwolin-161025041301/85/Dr-Ed-Wolin-July-16-2016-DC-Neuroendocrine-Tumor-Support-Group-Presentation-39-320.jpg)
Dr Ed. Wolin July 16 2016 DC Neuroendocrine Tumor Support Group Presentation
- 1. 2016 Capital Area carcinoid Survivors (CACS) Lecture Neuroendocrine Cancer Therapy - Where are we in 2016? Edward M. Wolin, M.D. Director, Neuroendocrine Tumor Program Montefiore Einstein Center for Cancer Care New York, NY
- 2. Incidence of GEP-NETs 0 1 2 3 4 5 6 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 SEER 9 1973 - 1991 SEER 13 1992 – 1999 SEER 18 2000 – 2011 Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26:3063-3072
- 3. NET Prevalence in the United States Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26:3063-3072
- 4. Classification of NET by Site Carcinoid Tumors Pancreatic NETs • Insulinoma • Glucagonoma • VIPoma • Pancreatic polypeptidom a Foregut • Thymus • Esophagus • Lung • Stomach • Duodenum Midgut • Appendix • Ileum • Cecum • Ascending colon Hindgut • Distal large bowel • Rectum
- 8. PaUent-Reported Time Between the First Symptom and a Diagnosis of NET 53% required >2 years for a diagnosis of NET and 34% required >5 years Edward Wolin, et al. Delays in Neuroendocrine Tumor Diagnosis: US Results From the First Global NET PaUent Survey. DigesUve Disease week, 2015 Total US sample (n = 758) 8% 18% 36% 34% 59.0 GI NETs 8% 15% 37% 36% 61.4 pNETs 6% 21% 40% 29% 53.4 Lung NETs 8% 24% 33% 31% 58.2 <6 Months 6 Month s – 5 Years ≥5 Years NET Diagnosis in the Following Time Period Don’t Know/ NA Mean (mont hs) Diagnosed at a NET Specialist Center 9% 8% 14%a 4%
- 9. Number of HCPs/Office Visits Prior to a NET Diagnosis 9 Number of HCPs involved in a NET diagnosis US PaDents, % US PaDents, % 8% 15% 16% 13% 10% 15% 8% 4% 11% 1 3 5 10-19 Don't know/ can't remember Mean, 5.7 HCPs 13% 18% 13% 6% 6% 6% 16% 20% 1-2 5-6 9-10 16+ Mean, 12.7 visits Number of visits to HCPs to receive a NET diagnosis Edward Wolin, et al. Delays in Neuroendocrine Tumor Diagnosis: US Results From the First Global NET Patient Survey. Digestive Disease week, 2015
- 10. Diagnoses Received Prior to a NET Diagnosis • 49% reported NET was not the iniUal diagnosis; most iniUally diagnosed with another GI condiUon • 38% were diagnosed with psychiatric condiUons, including anxiety and psychosomaUc disease • 78% did not suspect their symptoms were cancer related Edward Wolin, et al. Delays in Neuroendocrine Tumor Diagnosis: US Results From the First Global NET Patient Survey. Digestive Disease week, 2015 34% 7% 8% 8% 12% 13% 15% 19% 23% 26% 46% 49% Other Diabetes Rosacea Pneumonia Psychiatric disorder Ulcer Menopause Asthma IBDs (Crohn disease, ulceraUve coliUs) Anxiety/psychosomaUc-type condiUon GastriUs/other digesUve disorder IBS IBS diagnosis―GI NETs (61%) vs pNET (40%), lung NETs (18%) (P < 0.05) Asthma/pneumonia diagnosis― lung NETs (56%/35%) vs pNETs (11%/2%), GI NETs (11%/2%) (P < 0.05) US PaDents, %
- 11. And so these men of Hindustan Disputed loud and long, Each in his own opinion Exceeding stiff and strong, Though each was partly in the right And all were in the wrong. "The Blind Men and the Elephant John Godfrey Saxe (1816–1887).
- 14. What is Somatostatin? • Somatostatin (SST) is a peptide hormone. • It stops NET hormone production and cell division of NET cells. • The action of somatostatin occurs after it adheres to the somatostatin receptors (SSTR) on the cell membrane. • Very short-acting, with a 2-3 minute half-life.
- 15. SomatostaUn Analogs • ala gly cys lys asn phe phe cys ser thr phe thr lys trp D phe cys phe cys thr thr lys D trp Human somatostatin Octreotide Lanreotide Amino acids essenDal for receptor binding Half life: 3 minutes Half life: 90 minutes D βnal cys tyr cys val lys D trp
- 16. Derived from Pavel, ESMO 2014 AE Percentage Diarrhea 37.3% Steatorrhoea 39.3% Flatulence 28.1% Pain at injecDon site 28.1% Gall stones 17.9% Emesis 11.5% Hyperglycaemia 10.8% Bradycardia 4.3% CholangiDs 4.3% SepDcemia <1% Tolerability of SomatostaUn Analogs § Most side effects are transient § 30 years of experience § Very good long-term tolerability
- 18. PROMID: PFS Treatment Naïve Midgut NETs 0" 0.25" 0.5" 0.75" 1" 0" 6" 12" 18" 24" 30" 36" 42" 48" 54" 60" 66" 72" 78" 84" 90" HR="0.33"[95%"CI:"0.19–0.55]" P=0.000017" Propor;on"without"progression" Time"(months)" Octreo;de"LAR:"42"pa;ents"/"27"events" "Median"15.6"months"[95%"CI:"11.0–29.4]" " "Placebo:"43""pa;ents"/"41"events" "Median"5.9"months"[95%"CI:"5.5–9.1]" Rinke et al, JCO 2009
- 19. Placebo-Controlled study of LanreoDde AnDproliferaDve Response In paDents with enteropancreaDc NeuroEndocrine Tumors GEP-NETs, gastroenteropancreaDc neuroendocrine tumors; SC, subcutaneous. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. 1:1 12-24 weeks 1 12 24 36 48 72 96 (baseline) Study visits (weeks) Scan 1 Scan 2 LanreoUde Depot SC 120 mg q28 days Placebo SC q28 days Study design: Phase 3, 96-week, randomized, double-blind, placebo-controlled, mulUcenter study (14 countries: the US, India, and 12 European countries) PopulaDon: N=204 adults with well- or moderately differenUated, metastaUc, and/or locally advanced unresectable GEP-NETs, and Ki-67 <10% Treatments: LanreoUde Depot 120 mg (fixed dose) vs placebo every 28 days
- 20. CLARINET: Primary Efficacy Endpoint (PFS) Data are from the ITT populaUon. P-value derived from straUfied log-rank test; HR derived from Cox proporUonal hazards model. HR, hazard raUo; ITT, intenUon to treat; PBO, placebo; PD, progressive disease; PFS, progression-free survival. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. LanreoDde 32 events, 101 paDents Median PFS not reached Placebo 60 events,103 paDents Median PFS= 18.0 months [95% CI: 12.1, 24.0] 0 3 6 9 12 18 24 27 0 10 20 30 40 50 60 70 80 90 100 PaDents alive and with no progression (%) Time (months) 62% 22% LanreoDde 120 mg vs. PBO P <0.001 HR=0.47 [95% CI: 0.30, 0.73] Progression-free survival (ITT populaDon*) 101 94 84 78 71 61 103 101 87 76 59 43 40 Numbers of paDents at risk of death or PD 26 0 0
- 21. Summary of CLARINET GEP-NETs, gastroenteropancreaUc neuroendocrine tumors; NETs, neuroendocrine tumors; PFS, progression-free survival; SSA, somatostaUn analog. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. u CLARINET is the first Phase 3 tumor control trial of a somatostaUn analog which included all types of GEP-NET u ProlongaDon of PFS was significant, whether GEP-NET were well- or moderately differenUated, whether metastaUc or locally advanced, and whether high or low liver tumor burden u LanreoDde reduced risk of tumor progression or death by 53%. u PFS was > 96-weeks for lanreoUde vs 18 months for placebo u Hazard raUo favored lanreoUde in midgut and pancreaUc NET u Quality of life not significantly different or impaired by lanreoUde. u Overall survival not different between groups
- 22. ELECT Phase 3 Trial Met Primary Endpoint • ELECT® met its primary endpoint • A greater proporUon of paUents in the lanreoUde® arm experienced a complete response (40.7% vs. 23.2%, respecUvely) • Results largely consistent across subgroups ELECT: A phase III randomized double-blind placebo-controlled mulUnaUonal study of efficacy and safety of lanreoUde treatment for carcinoid syndrome in 115 paUents with neuroendocrine tumors (NETs)
- 24. SYMNET: Other Endpoints (GI Symptoms) Ruszniewski P, et al. Poster presented at ENETS. March 5-7, 2014; Barcelona, Spain. 4.4 3.9 2.3 38.8 15.3 25.2 0 5 10 15 20 25 30 35 40 45 50 Stool urgency (n=227) Stool leakage (n=255) Associated pain (n=258) Percentageofpatients Absent before treatment but present after Present before treatment but absent afterP<0.001 P<0.001 P<0.001 Changes in Stool Urgency, Stool Leakage, and Diarrhea-Associated Pain Post-LanreoDde Treatment
- 25. LanreoDde in Lung NET: SPINET Study Design • ObjecDve: Determine effecUveness of lanreoUde in controlling NET arising in lung. • Study design: Phase 3 Trial of lanreoUde 120 mg SQ every 28 days vs placebo* 2:1 randomizaUon in favor of lanreoUde. • *Cross-over for placebo arm if progression occurs. • PopulaDon: N=216 adults with locally advanced or metastaUc lung carcinoid (typical or atypical carcinoid) • Key eligibility criteria: – Must have measurable tumor on CT or MRI – Must have posiUve octreoscan or Ga-68 PET – Must not have been previously treated with OctreoUde or lanteoUde
- 26. SOM230–C2303 Pasireotide vs. Octreotide 0 3 6 9 12 Time, months 15 21 27 SurvivalProbability 0.0 0.2 0.4 0.6 0.8 1.0 Octreotide n/N = 20/56 Pasireotide n/N = 18/52 Censored Kaplan-Meier median PFS Pasireotide: 11.8 months, 95% CI [11.0–not reached] Octreotide: 6.8 months, 95% CI [5.6–not reached] Hazard ratio = 0.46, 95% CI [0.20–0.98] Total events = 38 2 P = 0.045 (log-rank test) Wolin et. al., A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-relatedsymptoms inadequately controlled by somatostatin analogs. J Clin Oncol 31, 2013 (suppl; abstr 4031)
- 28. Schematic Representation of a Drug for Imaging and Targeted Therapy Molecular Address • Antibodies, minibodies, Affibodies, SHALs, Aptamers • Regulatory peptides and analogs thereof • Amino Acids Target • Antigens (e.g. CD20, HER2) • GPCRs • Transporters Reporting Unit • 99mTc, 111In, 67Ga • 64Cu, 68Ga • Gd3+ Cytotoxic Unit • 90Y, 177Lu, 213Bi • 105Rh, 67Cu, 186,188Re Courtesy Helmut Mäcke (modified) Targeted Molecular Imaging and Therapy The Key-Lock Principle Lock Key 68Ga, 90Y, 177Lu pharmacokineDc/biodistribuDon modifier Chelator Linker Ligand Target
- 29. A brief overview of 177Lu- DOTATATE • 177Lu-DOTATATE belongs to an innovative drug category called PRRT (Peptide Receptor Radionuclide Therapy). PRRT involves the systemic administration of a specific radiopharmaceutical to deliver cytotoxic radiation to a tumor. • 177Lu-DOTATATE is composed of a lutetium radionuclide chelated to a peptide. Lutetium emits high energy electrons (therapy) and gamma rays (imaging). • The peptide is designed to target somatostatin receptors with a high binding affinity. The affinity for SSTRs and the specificity of binding enables a high level of specificity in the delivery of radiation to the tumor 29
- 30. Lutathera® Mechanism of Action 30 Intravenous injection Concentration into neuroendocrine tumor (NET) sites Lutathera binds to somatostatin receptors type 2 (sstr2) overexpressed by NETs Lutathera is internalized in the NET cell Lutathera delivers radiation within the cancer cell Radiation induces DNA strand breaks causing tumor cell death
- 32. Progression-Free Survival 32Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna Hazard Ratio [95% CI] 0.209 [0.129 – 0.338] p < 0.0001 N = 229 (ITT) Number of events: 90 • 177Lu-Dotatate: 23 • Oct 60 mg LAR: 67 All progressions centrally confirmed and independently reviewed for eligibility (SAP) Octreotide LAR 60 mg Median PFS: 8.4 months 177Lu-Dotatate Median PFS: Not reached
- 33. Overall Survival (interim analysis) 33Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna N = 229 (ITT) Number of deaths: 35 • 177Lu-Dotatate: 13 • Octreotide 60 mg LAR: 22 P < 0.0186 0. 5
- 34. Inclusion Criteria Expanded Access 1. Presence of metastatic or locally advanced, inoperable (curative intent) midgut carcinoid tumor. 2. Ki-67 index < 20%. 3. Patients progressive on SSA (any dose) at the time of enrollment Recist NOT required) 4. Patients > 18 years of age. 5. Target lesions overexpressing somatostatin receptors according to an appropriate imaging method (e.g. 111In-pentetreotide (Octreoscan) imaging or 68Ga-DOTA0-Tyr3-Octreotate imaging) (Bodei et al., 2014).
- 35. PepUdes and Receptors in Image-Guided Therapy: TheranosUcs of Neuroendocrine Neoplasms R. Baum et al. Semin Nucl. Med 42:190-207 (2012) Figure 7 Molecular response as demonstrated by receptor PET/CT using the SMS analog 68Ga-DOTANOC in a patient with liver metastases of a NEN before and after the first and second cycle of peptide receptor radionuclide therapy (PRRNT); relapse in the liver (after complete remission as shown by CT and PET) is first detected by SMS-receptor imaging (molecular response precedes morphology). Peptides and receptors in image-guided therapy 199
- 36. Added Value of 68Ga-DOTATATE PET/CT Mojtahedi A, Am J Nucl Med Mol Imaging 2014;4(5):426-434
- 37. Impact of 68Ga-DOTATATE PET/CT • 100 consecuUve pts scanned, and referring physicians completed 88 pre- and post-scan quesUonnaires (88%). • Intended management changed in 53 of 88 (60%) of pts. • 23% scheduled to undergo chemotherapy switched to treatments without chemotherapy. • 7% switched from watch-and-wait to other treatment. • 6% switched from treatment strategy to watch-and-wait. Ken Herrmann, Johannes Czernin, Edward M. Wolin, et al. Impact of 68Ga-DOTATATE PET/CT on the Management of Neuroendocrine Tumors: The Referring Physician’s PerspecUve. J Nucl Med 2015; 56:70–75.
- 38. RADIANT-3 Study Design Everolimus 10 mg/d + best supportive care* n = 207 Placebo + best supportive care* n = 203 Multi-phasic CT or MRI performed every 12 weeks Treatment until disease progression Patients with advanced pNET, N = 410 Stratified by: • WHO PS • Prior Chemotherapy Crossover 1:1 Concurrent somatostatin analogs allowed R A N D O M I Z E Primary endpoint: • PFS (RECIST) Secondary endpoints: • Response, OS, biomarkers, safety, and PK Randomization August 2007 - May 2009 Phase III Double Blind Placebo Controlled Trial
- 39. RADIANT-3 PFS by Central Review* * Independent adjudicated central review committee • P-value obtained from stratified one-sided log rank test • Hazard ratio is obtained from stratified unadjusted Cox model Kaplan-Meier medians PFS Everolimus: 11.4 months Placebo: 5.4 months Hazard ratio = 0.34; 95% CI [0.26-0.44] P-value: <0.0001 No. of patients still at risk Everolimus Placebo 207 203 187 180 152 99 126 60 117 52 81 22 49 12 36 5 27 3 22 1 10 1 6 1 2 0 0 0 Time (months) 100 80 Percentageevent-free Censoring Times Everolimus (n/N = 95/207) Placebo (n/N = 142/203) 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26
- 40. RADIANT-4 Study Design *Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worst prognosis) - lung, stomach, rectum, and colon except caecum. Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Endpoints: • Primary: PFS (central) • Key Secondary: OS • Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Everolimus 10 mg/day N=205 Treated until PD, intolerable AE, or consent withdrawal Patients with well- differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N=302) • Absence of active or any history of carcinoid syndrome • Pathologically confirmed advanced disease • Radiologic disease progression in ≤ 6 months 2:1 R A N D O M I Z E Placebo N=97 Stratified by: • Prior SSA treatment (yes vs. no) • Tumor origin (stratum A vs. B)* • WHO PS (0 vs. 1)
- 41. RADIANT-4 Primary Endpoint: PFS by Central Radiology Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. CI, confidence interval; HR, hazard ratio. 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0Placebo Everolimus No.of patients still at risk 0 2 4 6 8 10 12 15 18 21 24 27 30 Months 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofProgression-freeSurvival(%) Kaplan–Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Censoring Times Everolimus (n/N = 113/205) Placebo (n/N = 65/97)
- 42. Dual Kinase mTOR InhibiDon in Carcinoid • CC-223 inhibits 2 enzymes – TORC-1 and TORC-2 (Everolimus, is a TORC1-selecUve inhibitor.) Phase 1b trial of CC-223 in 40 pts with well-differenUated NET • SymptomaUc improvement in 92% occurred quickly and persisted during the trial. • Carcinoid syndrome markedly improved: reducUon of flushing (80%) and reducUon of bowel movements (57%). • ReducUon in FDG-PET glucose uptake (≥ 25% SUV) at day 15 was observed (57%). • Long progression-free survival observed. (Wolin, E. et al. Phase 1 expansion study of an oral TORC1/TORC2 inhibitor (CC-223) in non- pancreaDcneuroendocrine tumors (NET). NANETS. Oct. 4, 2013)
- 43. RaDonale for Alpelisib (BYL719) + Everolimus in pNET • Everolimus is acUve against mTORC1 only. • Low response rate to everolimus may reflect the drug’s inability to prevent mTORC2-mediated acUvaUon of Akt. • PI3K/Akt/mTOR acUvaUon and reacUvaUon could potenUally be avoided through the concomitant use of PI3Kand mTOR inhibitors. • Alpelisib and everolimus each administered daily at the dose from previously completed 1a trial in new trial opening at Montefiore. Wolin, E. PI3K/Akt/mTOR Pathway Inhibitors in the Therapy of PancreaUc Neuroendocrine Tumors. Cancer Lev. 2013 Jul 10;335(1):1-8.
- 45. Pazopanib (CALGB 81103) study Design Randomized phase II trial in CARCINOID R A N D O M I Z E Pazopanib 800 mg PO qD No breaks N≈150 • Progressive, advanced carcinoid tumor • Functional or non-functional • Concurrent octreotide OK if PD documented 1° EP PFS (Central review) Placebo Option for cross- over at progression 1 cycle=28 days CT scan q 12 wk
- 46. Study design Presented By James Yao at 2015 ASCO Annual Meeting
- 47. Conclusion Presented By James Yao at 2015 ASCO Annual Meeting
- 48. CALGB 80701 (Alliance): Schema<br />N=148 Presented By Diane Reidy at 2015 ASCO Annual Meeting
- 49. CALGB 80701: Efficacy Presented By Diane Reidy at 2015 ASCO Annual Meeting
- 51. Chemotherapy OpUons for GEP-NETs Regimen Tumor Type n TTP or PFS (mo) OS (mo) RR (%) Reference Cytotoxics Streptozocin/5-FU vs. Carcinoid and pNET 42 Not reported Not reported 33 Moertel, 1979. Streptozocin/ Cyclophosphamide* 47 26 Streptozocin/ Doxorubicin vs. pNET 38 20 26.4 69 Moertel, 1992. Streptozocin/5-FU vs. 34 6.9 16.8 45 Chlorozotocin 33 6.9 16.8 30 Temozolomide / Capecitabine pNET 30 18 na 70 Strosberg, 2011. * RegistraUon trial leading to FDA approval
- 52. Arm A: Everolimus Everolimus (10 mg, daily) (10 mg, daily) Arm B: STZ-5FU STZ-5FU Sequence mTOR Study (SEQTOR) Everolimus - STZ 5-FU in Progressive pNET • Accrual goal = 180 pts • Study populaUon: progressive, metastaUc pNET, 1st line axer SSA, G1/G2 • Primary EP: PFS2; Secondary EP: OS, RR, biochemical response • Study is ongoing Course 1 Progression Course 2 Slide courtesy of R. Salazar,, Barcelona NCT02246127
- 54. Targeted Agents in Early Clinical Trials in NETs Drug Target(s) BEZ235 Dual PI3K/mTOR Axitinib Multiple kinases including VEGFR2 Ibrutinib BTK MK2206 Akt LEE011 CDK 4/6 Dovitinib FGFR Pembrolizumab PD-1 Ziv-aflibercept VEGF, PLGF Entcretinib TRK, ROS1, ALK Nintadanib VEGFR, FGFR, PDGFR Cerfilzomib 20S proteosome
- 56. Telestar Study of Telotristat R Telotristat eDprate 500 mg TID* (n=45) Telotristat eDprate 250 mg TID (n=45) Placebo TID (n=45) 3- to 4- week run- in (n=135) Telotristat eDprate 500 mg TID All patients required to be on SSA at enrollment and continue SSA therapy throughout study period Evaluation of primary endpoint: Reduction in number of daily BMs from baseline (averaged over 12- week double-blind treatment phase)
- 57. TELESTAR: Mean Absolute Change in Urinary 5- HIAA (mg/24 h) from Baseline to Week 12 575-HIAA, 5-hydroxyindoleacetic acid; SSA, somatostatin analog. 11.47 -40.13 -57.73 -60 -50 -40 -30 -20 -10 0 10 20 Placebo Telotristat etiprate 250 mg Telotristat etiprate 500 mg MeanUrinary5-HIAAChangefrom Baseline(mg/24h) n=29 n=32 n=31
- 58. Telotristat Results of Phase 3 Study • Telotristat significantly reduced BM frequency by an addiUonal 35% in paUents already taking somatostaUn analogs, from 6 BM/day to 3.8 BM/day. • Durable response in over 40% of paUents (defined as >30% reducUon in BM frequency for >50% of the double-blind study) • Urinary excreUon of 5-HIAA was reduced by 58% comparing baseline with week 12. Netest.pptx
- 59. § Multi Gene expression assay performed on peripheral blood (liquid biopsy) § Developed specifically for neuroendocrine tumors § Provides a quantitative score that reflects disease activity § Verified and validated across 3,000 clinical samples The NETest from Wren Laboratories
- 60. NETest Accuracy – Limit of Detection Comparison with imaging Modlin et al. Plos One 2013 e63364 Limit of DetecDon = 1 NET cell/ml CT Scan 10mm3 = 1,000,000,000 cells NETest 5.5 liters of blood (70kg male) NETest = ~125,000 x more sensitive than imagery
- 61. Stable Disease Progressive Disease p<0.001, HR 31.8 p<0.01, HR 14.6 95% predictive accuracy92% NETest and Somatostatin Analog Efficacy Cwikla J et al. JCEM 2015; 100:E1437-45 NETest correlates with SSA efficacy